The inherited spinocerebellar ataxias (SCAs) are a heterogenous group of disorders characterized by variable degrees of degeneration of the cerebellum, spinal tracts, and brain stem. The primary ataxias are currently, for the most part, poorly understood. This multidisciplinary Program Project proposal is designed to address the SCAs using genetic, molecular, and pathophysiological approaches. This proposal brings together a group of investigators from the clinical and basic sciences committed to obtaining new information that will further our understanding of the hereditary ataxias. The Program consists of two support cores, administrative and clinical, and four scientific projects. The long term goals of these projects are: Project 1: To develop and characterize a transgenic mouse model of spinocerebellar ataxia type 1 (SCA1). This will be achieved by using the SCA1 gene recently identified by Dr. Orr and colleagues. Project 2: To examine the molecular aspects of the CAG trinucleotide repeat unstability associated with SCA1. Molecular studies will be performed using patient sperm, cell lines, and transgenic mice developed in Project 1. Project 3: To use a positional cloning strategy to localize and isolate the gene affected in a large ten generation kindred with an autosomal dominant SCA, designated as LSCA. By linkage analysis, LSCA is distinct from SCA1, SCA2, and Macchado-Joseph disease. Project 4: To study the metabolic anatomy and pathophysiology of hereditary ataxias (SCA1 and LSCA) using the quantitative imaging techniques of [18F]fluorodeoxyglucose (FDG) and [150]Water positron emission tomography. (PET) Core A (Clinical): To provide several important clinical supportive functions, including neurological assessments, maintenance of a Ataxia Database, autopsies, and collection of sample material for future genetic studies.